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THE CHANGING FACE OF VIRAL
HEPATITISD. Robert Dufour, MD, FACB, FCAP
Consultant PathologistAttending, Liver ClinicVAMC, Washington DC
Emeritus Professorof Pathology
• Acute viral hepatitis has become an increasingly rare disease
• Reported incidences are at their lowest recorded values for all major viruses
• Childhood immunization has led to near universal immunity to HBV in USA
• From this standpoint, we are winning the war against viral hepatitis
SIGNIFICANCE
Source: CDC Viral Hepatitis Surveillance and Statistics
Source: CDC Viral Hepatitis Surveillance and Statistics
Source: CDC Viral Hepatitis Surveillance and Statistics
• Chronic HBV and HCV remain common• In US, chronic HCV affects at least 2% (2.7
million individuals), while chronic HBV affects approximately 1 million (85% born outside US)
• Both may lead to cirrhosis (20-30% after 20 yr), hepatocellular carcinoma (HCC) (3-5%/yr once cirrhosis present)
SIGNIFICANCE
SIGNIFICANCE• Symptoms of chronic infection minimal, most unaware
until complications develop• Cirrhosis expected to increase 4-fold over next 30 years• HCC incidence doubled over past 20 years, expected to
increase further 3x; at VAMC DC, have gone from 5-6/yr to 3-4/month
• Effective therapies available for HBV, HCV
HEPATITIS A, E
HEPATITIS A• Peak age incidence now 20-35
• Major risk factors injection drug use, males having sex with males
• IgM anti-HAV now largely (62%) false positive; CDC recommends use only in clinical setting of acute hepatitis (MMWR 2005;54:453)
HEPATITIS E• Recognized as an enteric virus in locations with poor hygiene;
anti-HEV < 5% in children, but 30-60% in young adults, men > women
• High mortality in pregnant women (30-50%); low mortality rate otherwise (as with HAV)
• As with HAV, thought not to have a chronic phase
• In developed countries, felt to not occur without travel to endemic areas
HEPATITIS E• HEV is endemic in pigs and rats worldwide• Link between pork ingestion, death from chronic liver
disease in 18 countries• Studies have shown high frequency (10-20%) anti-HEV in
blood donors in western countries• Has raised issue of zoonotic spread of HEV, but known cases
of HEV difficult to link to pork ingestion or pig exposure
HEPATITIS E• In past few years, well documented case series of HEV in
Europe with the same genotype as found in animals (J Med Virol 2008;80:646); age range similar but mortality higher (10%), esp. in those with chronic liver disease (70%)
• Anti-HEV more common in IV drug users; post-transfusion cases in several countries
• Recently, reports of chronic HEV in liver transplant recipients (Liv Transpl 2008;14:547)
HEV DIAGNOSIS• IgM anti-HEV best test for acute infection; as with HAV,
false positive possible, may be false negative in early stage
• IgG anti-HEV long-lasting (but probably not life-long); rise in titer can also be used for acute infection diagnosis
• HEV RNA viremia persists for an average of 4 weeks in acute infection; no commercial labs in US currently offer HEV RNA, however
HEPATITIS B
• Partially double-stranded DNA virus, belongs to family hepadnaviridae
• Peculiar pattern of coding, replication unique among viruses
• Virus is not hepatotoxic; damage occurs from T-cell response to the virus
• Virus may be carcinogenic (? Related to HBV X antigen)
HBV BIOLOGY
HBV Replication
Circulating HBV
Infection Reservoir
Replication HBV mRNA
ReverseTranscriptase
RNA-DNA Hybrid
Partially ds-DNA Pre-S
Free HBsAg
Free HBeAg
HBVparticle
RnaseDNA Polymerase
Partially ds-DNA
Covalently ClosedCircular (ccc) DNA
HBV core AgHBVpolymeraseHBV
mRNAHBVmRNA
HBV BIOLOGY• RNA replication leads to high rate of mutations (not as high as
HIV, though)• Certain sites of mutation more common - #1 is stop codon in
pre-core coding region, also commonly affect core promoter region; both decrease production of HBeAg (latter may also increase risk of HCC)
• Mutations commonly induced by some reverse transcriptase inhibitors used to treat virus
OUTCOME• Outcome mainly dependent on age at exposure, less affected
by immune status
• In infants, 95% chronically infected; in young children, 30-50% chronically infected
• In adults and adolescents, HBV is usually “cleared” after exposure, < 5% chronically infected (may be < 1%)
• In immunosuppressed adults and adolescents, 10-20% chronically infected
HBVExposure
HBV Outcomes in Infants and Children < 5
Immune Control
Loss of HBsAgImmune Tolerance
Immune Active
5%
1-2%/yr
95%
50-70% 30-50%
7-8%/yr
0.5-1%/yr
7-8%/yr1-2%/yr
HBVExposure
Outcomes of HBV exposure in Adults
Immune Control
Loss of HBsAgAcute
Hepatitis
Immune Active
10-20% (low immune status)
30-50%50-70%
7-8%/yr
1-2% (normal immune status)
? 0.5%
1%/yr
0.5%/yr
HBV SEROLOGIC TESTS• Complicated set of markers lead to confusing patterns
• Even more complicated by increased knowledge of biology of HBV
• Still most widely used tests for HBV diagnosis, becoming less widely used for monitoring of treatment
HBsAg• Responsible for genotypes of HBV; common “a” determinant in all
genotypes
• Vaccine response mainly to “a” determinant
• Mutants in “a” determinant may not be recognized by vaccine, HBsAg serologic tests
• Multiple mutants occur; none recognized by all current HBsAg test kits
• Little data, but mutants usually occur with wild-type virus, in low amounts, and rare as sole infection
ISOLATED ANTI-HBc• Early in viral clearance (“Core window” in acute hepatitis,
during recovery)
• Many years following infection; especially common in HCV infected
• Failure to develop anti-HBs (?especially in immune deficient)
• False positive result (post-influenza vaccine, other states)
• HBsAg mutants (recent study – 3%)
HBeAg• Produced along with viral particles, but not part of virus; not
needed for replication, function uncertain (? immune response)
• Correlates with replicating virus in untreated; loss usually = low level (or no) viremia
• Not produced by pre-core or core promoter mutants• During treatment, loss indicates likelihood of continued
response after discontinuation
HBV DNA in HBeAg Pos vs Neg
0%
20%
40%
60%
80%
100%
< 2 2 3 4 5 6 > 7
Log HBV DNA (IU/mL)
HBeAg Pos HBeAg neg
Source: VA Medical Center Washington DC
ANTI-HBe• Appears with loss of HBeAg, indicating loss of
circulating virus• Formerly used to indicate transition to carrier state• Also present if HBeAg lost due to development of pre-
core mutant strains• Usually persists for life, but some lose anti-HBe and re-
develop HBeAg (and re-activate HBV DNA production)
HBV DNA• Assays have marked difference in detection limit;
reported in pg/mL, copies/mL (1 pg = 285,000 copies)
• WHO standard now used for most assays (IU/mL), but correlation not linear (unresolved issue)
• Most with chronic hepatitis have > 105 copies/mL (often > 109); levels < 102 thought to have low transmission risk
Lower Detection Limits for HBV DNA
Method Detection Limit IU/mL pg/mL
Hybrid Capture 1.0 * 106 10.5
Branched DNA 2.0 1 * 105 2.5 Liquid Hybridization 4.0 * 103 0.02 Branched DNA 3.0 2.0 * 103 0.01 PCR 1-2 * 102 0.001 Real Time PCR 2-5 * 101 0.0001
HBV OUTCOMES & SEROLOGYState HBsAg Anti-
HBsAnti-HBc
HBeAg Anti-HBe
HBV* DNA
ALT
Acute hepatitis Pos Neg Pos‡ Pos Neg > 106
Immune tolerance
Pos Neg Pos Pos Neg > 106 Nl
Immune active Pos Neg Pos Pos Neg > 106
HBeAg + hepatitis
Pos Neg Pos Neg Pos < 106
Immune control Pos Neg Pos Neg Pos < 102† Nl
Occult Neg Pos Pos Neg Pos < 102† Nl
*In IU/mL; ‡ Typically IgM anti-HBc positive; †May be positive with very sensitive techniques in serum or liver biopsy
HBV REACTIVATION• Return of HBV replication where previously inactive• More common form: HBsAg positive but in immune
control phase, virus again replicative (often with return of HBeAg)
• Less common form: HBsAg negative, anti-HBc positive when viral replication returns (sometimes termed seroreversion)
HBV REACTIVATION• Usually occurs in setting of immune suppression (HIV,
transplant, steroids, cancer chemotherapy); frequency higher with more intense immune suppression
• While viral replication itself, immune response to virus often causes severe liver injury with recovery of immune function
• High morbidity and moratlity
ImmuneSuppression
HBV Reactivation
Immune Control
Anti-HBc posHBsAg neg
Acute Hepatitis
Acute liver failure
30-50%
1-2% 20%
10-20%Restore
Immunity
HBV REACTIVATION• Treatment of HBsAg positive pre-immune
suppression highly effective• Associated with reduced overall and liver-related
mortality• Recent guidelines suggest routine testing for HBsAg
and anti-HBc before immune suppression, treatment if HBsAg positive; less clear for anti-HBc positive
HEPATITIS C
HCV BIOLOGY• Single strand RNA virus, part of flaviridae family
(WNV, yellow fever, dengue)
• Relatively new virus (? Late 1880’s)
• High rate of spontaneous mutation leads to unique pattern of quasispecies in each individual after initial infection
• Virus not cytopathic, destroyed by T-cell response
• Major screening test for HCV, detects antibody to 1 of 4 HCV antigens
• Two basic versions (2nd, 3rd generation) in use; 2nd sl less sensitive, not positive till avg 12 wk after exposure, 3rd sl less specific, pos. avg 9 wk.
• EIA tests less specific than CA, MEIA versions for same generation, but false positive results relatively common with all
ANTI-HCV
ANTI-HCV• Most false positive are weakly positive
• Weak positive defined as 3.8 by EIA, 8 by Ortho, 10 by Abbott, < 11 by Siemens
• Majority of weakly positive are negative on other anti-HCV assays or on confirmatory tests
• CDC recommends performance of RIBA on all weakly positive before reporting
Positives defined by S/C ratio
OR
OR
RIBA for anti-HCV
Screening test for Anti-HCV ReportNegative
Report ReportReport
Positive IndeterminateNegative
HCV RNA
All positives
RIBA for anti-HCV
Report
ReportReport Report
Negative
Positive
IndeterminateNegativePositive
Positive
Report
Positives with high S/C ratio Positives with low S/C ratio
HCV RIBA Equivalent to western blot; uses purified HCV antigens from yeast recombinants
Positive: Ab to at least 2 Ag Indeterminate: Ab to one Ag, or to yeast marker (SOD) plus HCV Ags
Most patients with high titer anti-HCV have positive, usually used only when low titer anti-HCV (or in blood donors)
TREATMENT OF CHRONIC
HBV AND HCV
ACUTE HEPATITIS• No treatment is recommended for acute HBV (except in
rare cases with acute liver failure)• Acute HCV usually not recognized; when diagnosed
(e.g., post-needlestick) several studies suggest that treatment with interferon for 6 months can clear virus in 90-100% of cases, compared to 50% with no treatment
• Treatment effective in first 6 months
• Seven agents approved: interferon (std., pegylated), lamivudine, adefovir, telbivudine, entecavir, tenofovir; last two most used
• Combination treatment not currently used• Response rate to IFN low in those with normal ALT, or viral load <
105 or > 1010 copies/mL• “Ideal” response: nl ALT, loss of HBeAg and HBV DNA, and
development of anti-HBe• Rarely, HBsAg is also cleared
CHRONIC HEPATITIS B
• Histologic improvement usually seen with clearance• Relapses after treatment can occur• Success rate with 1 yr Rx about 30-40%• With oral agents, increasing treatment to 3-4 yrs increases
response to 70%, but resistant mutants also increase (28% with 5 yr treatment for adefovir, 70% for lamivudine, < 5% for entecavir, tenofovir [2 yr data only])
CHRONIC HEPATITIS B
• In HBeAg +, ALT (> 1.5 x nl), or advanced biopsy findings (mod or higher inflammation, stage II or higher fibrosis), esp if > 40 yrs old
• In HBeAg -, similar, but also based on VL (treatment not recommended if < 2000 IU/mL, or if < 20,000 IU/mL and biopsy shows minimal damage), esp. if > 40 yrs old
• Patients not treated should be monitored, as changes in status are common
TREATMENT INDICATIONS
Copyright restrictions may apply.Chen, C.-J. et al. JAMA 2006;295:65-73.
Cumulative Incidence of Hepatocellular Carcinoma by Serum HBV DNA Level at Study Entry
104-105
< 104
105-106
> 106HBsAg pos > 106
105-106
104-105
< 104
HBeAg neg
• In those with cirrhosis, reduces likelihood of complications (including HCC), can delay or eliminate need for transplant
• Histologic improvement (including decreased fibrosis) common with viral response
• Felt to have similar benefits in those with less advanced disease, but long term data lacking (although histologic improvement documented)
TREATMENT BENEFITS
• Loss of HBV DNA (< 100 IU/mL) is achieved in 70-80%; measurable HBV DNA indicates high rate of relapse
• Timing of measurements unclear; one study suggests response highest if < 100 at 12 wk
• If < 2 log decrease by 3 mo, we generally switch to another agent
• If viral load detectable but > 100, we usually continue treatment, re-evaluate at 6 mo
MONITORING Rx
• In HBeAg + with loss HBV DNA, serial monitoring of HBeAg status prognostic; if HBeAg lost (and anti-HBe develops), treatment can be D/C after 6-12 mo with 80% success
• In HBeAg – (or HBeAg + who do not convert), D/C treatment leads to rapid reactivation of HBV replication; treatment usually long-term in these patients
MONITORING Rx
CHRONIC HEPATITIS C• Current treatment of choice is pegylated interferon plus ribavirin
• Treatment usually for 24 wks with genotype 2 or 3, 48 wks for other genotypes
• Goal of treatment is clearance of virus that persists after therapy stopped
• Response rate is about 40% with genotype 1, 70-80% with genotypes 2, 3, 60-70% with genotype 4
CHRONIC HEPATITIS C• Effectiveness monitored at 12 wk; failure to clear virus or
fall by > 2 logs (early virologic response, EVR) indicates < 5% likelihood of success
• Success evaluated 6 mo post-Rx as absent HCV RNA by sensitive method (sustained virologic response, SVR)
• In those with SVR, likelihood of recurrent viremia < 1%; however, virus persists in mononuclear cells in most
CHRONIC HEPATITIS C• Intermediate time points provide additional data and can be used
to customize treatment duration• Rapid virologic response (RVR): absent HCV RNA after 4
weeks of treatment (~90% SVR)• In those still positive at 4 weeks but negative at 8 weeks, 70%
SVR rate• In those with EVR but viral load measurable at 8 wk, longer
treatment (72 wk G1, 48 wk G2/3) improves response rate
RECENT ARTICLES• HBV Guidelines:
– AASLD - Hepatology 2007;45:507– CDC Recommentations: MMWR 2008;57(RR-08)
• HCV Guidelines:– AASLD - Hepatology 2004;39:1147– CDC (on lab testing) MMWR 2003;52 RR-3
• Reactivation Review– Ann Intern Med 2008;148:519
• HEV Review– Lancet Infect Dis 2008;8:698